The response of the lungs in patients with significant exposure to asbestos is characterized by a prolonged, intense inflammatory response that often results in pulmonary fibrosis. The release of TNF-? by alveolar macrophages plays an integral role in the inflammatory response that occurs in the lungs of patients with asbestosis. A characteristic feature of the alveolar macrophages is that they spontaneously release TNF-? and they resemble monocytes. Data from the investigators show that monocytes produce a significant amount of TNF-? when stimulated in vitro with asbestos. In contrast to most stimuli, our novel data demonstrates that the p38 MAP kinase is a positive regulator and the ERK MAP kinase is a negative regulator of TNF-? production in response to asbestos stimulation. However, limited data is available on the upstream signaling pathways linking asbestos with TNF-? expression. The GTPase Rac1 is an upstream second messenger that plays an important role in inflammation. In this regard, our novel data also show that TNF-? production is augmented in monocytes over expressing Rac1, and Rac1 null mice are protected from developing pulmonary fibrosis after exposure to asbestos. The investigators hypothesize that Rac1 plays a pivotal role in differentially modulating MAP kinase activation and that this differential activation is critical for TNF-? gene expression in human monocytes stimulated with asbestos. In addition to our in vitro model, we will explore this in alveolar macrophages obtained from asbestosis patients and in an animal model of asbestosis. In Aim 1 we will focus most of our studies on the mechanism(s) by which Rac1 differentially modulates MAP kinase pathways. These studies will also determine if p38 inhibits expression of the ERK kinase by activating a dual specificity phosphatase. The use of wild-type and Rac1 null mice in a murine model of asbestosis will provide biological relevance. In Aim 2, we will first determine if Rac1 modulates TATA-binding protein (TBP) phosphorylation, which is essential for TNF-? gene expression. Since Rac1 has differential effects on MAP kinase activation, we will determine if an increase in p38 and a decrease in ERK activity are necessary for optimal TNF-? production. The investigators will also compare alveolar macrophages from asbestosis patients to normal subjects in regard to Rac1, p38, and ERK activity. The exposure of wild-type and Rac1 null mice to asbestos to determine the effect on the development of interstitial fibrosis will provide additional biological relevance.